A limitation factor in the field of cystic fibrosis (CF) has been the ineffectiveness of the CF mouse model. The recent development of the CF pig and ferret has provided additional animal models that can potentially be used to elucidate CF pathology further and to develop therapies for CF. In our preliminary work, we generated CFTR KO rabbits by using Cas9. Encouragingly CFTR null rabbits mimic human patients in several aspects including spontaneous lung infection. It is recognized that the majority of human CF patients (>70%) carry CFTR ?F508 mutation. It is further realized that CFTR?F508 protein from other species shows differences in its processing compared to human CFTR?F508 (hCFTR?F508). Thus, studies on understanding CF and developing new treatments would be further expedited with a new rabbit model expressing the hCFTR?F508. In Aim 1, we propose to generate hCFTR?F508 rabbits. In Aim 2, we propose to express WT rabbit CFTR (rbCFTR) in hCFTR?F508 rabbits to increase the life expectancy of the CF rabbits which is critical to fully recapitulate CF disease progression in the animals. The success of proposed work will provide an animal model for the characterization of CF pathology and the underlying molecular mechanisms. The development of therapeutic regimens would also be greatly facilitated by a model that displayed characteristic CF pathology.